Process for the manufacture of 6-acylamino-2,2-dimethyl-3-hydroxy penam compounds

ABSTRACT

THE INVENTION CONCERNS THE MANUFACTUR OF 6-ACYLAMINO-2,2-DIMETHYL-3-HYDROXY-PENAM COMPOUNDS BY REDUCTIVE CLEAVAGE OF THE ESTERFIED CARBOXYL GROUPING IN A 6-ACYLAMINO-2,2-DIMETHYL - 3 - ARYLCARBONYLMETHOXYCARBONYL-AMINO-PENAM COMPOUND IN THE PRESENCE OF WATER.

United States Patent Oflice 3,808,201 Patented Apr. 30, 1974 3,808,201PROCESS FOR THE MANUFACTURE OF 6-ACYL- AMINO 2,2 DIMETHYL-S-HYDROXYPENAM COMPOUNDS Karl Heusler, Basel, Switzerland, and Robert BurnsWoodward, Cambridge, Mass., assignors to Ciba-Geigy Corporation,Ardsley, N.Y.

No Drawing. Filed May 26, 1971, Ser. No. 147,180 Claims priority,application Switzerland, June 5, 1970, 8,467/ 70 Int. Cl. C07d 99/16 US.Cl. 260--239.1 11 Claims ABSTRACT OF THE DISCLOSURE The inventionconcerns the manufacture of 6-acylamino-2,2-dimethyl-3-hydroxy-penamcompounds by reductive cleavage of the esterified carboxy] grouping in a6-acylamino-2,2-dimethyl 3 arylcarbonylmethoxycarbonyl-amino-penamcompound in the presence of water.

The Pat. No. 3,705,160 (application No. 842,028) filed July 15, 1969 byKarl Heusler et a1.) proposes a process for the manufacture ofthiazacyclic hydroxy compounds, especially of 6N-Ac-amino-3-hydroxy-2,Z-dimethyl-penam compounds of the formula t CH- HCH Ae-Nfi s (I) in which Ac represents the acyl residue of an organicacid, and of O-esters of such compounds, wherein in a penam compound ofthe formula 3 NH-X 11-011 Ae-N s 11 in which X together with thecarbonyl grouping represents an esterified carboxy or thiocarboxy groupcapable of being split under neutral or weakly acidic conditions, thegroup of the formula --C(=O)X is split under neutral or weakly acidicconditions in the presence of water, and, if desired, in a resultingcompound the free hydroxyl group in 2-position is acylated, and/or, ifdesired, in a resulting compound, which contains an acylamino groupingcontaining protected functional groups, such groups are liberated,and/or, if desired, a resulting isomer mixture is resolved into theindividual isomers.

A preferred group X is the residue of the ;-formula OR,, where R standsfor -a 2-halogeno-lower alkyl residue, and such a residue may containone, two or more halogen atoms, that is to say chlorine, bromine oriodine atoms, the 2-chloroand 2-bromo-lower alkyl residue containingadvantageously several, preferably three, chlorine or bromine atoms,whereas a 2-iodo-lower alkyl residue may contain a single iodine atom.The residue R preferably represents a 2-polychloro-lower alkyl, such as2-polychloroethyl residue, in the first place the 2,2,2-trichloroethylresidue, or the 2,2,2-trichloro-l-methylethyl residue, but may also be,for example, a 2-polybromo-lower alkyl, such as the 2,2,2-tribromoethylresidue, or a 2-iodo-lower alkyl, for example, the 2-iodoethyl residue.

According to the process of the Pat. No. 3,705,160 the preferred groupof the formula -NHC(-=0)OR is eliminated by treatment with a chemicalreducing agen in the presence of water.

The present invention is based on the observation that compounds of theformula I are also obtained, when a penam compound of the Formula H, inwhich X stands for the residue of the formula -OR wherein R,, representsan arylcarbonylmethyl group, in which aryl is an optionally substitutedaromatic hydrocarbon residue, is treated with a chemical reducing agentin the presence of water, and, if desired, in a resulting compound thefree hydroxyl group in Z-position is acylated, and/or, if desired, in aresulting compound, which contains an acylamino grouping comprisingprotected functional groups, such groups are liberated and/or, ifdesired, a resulting isomer mixture is resolved into the individualisomers.

In an arylcarbonylmethyl group R aryl stands for a bicyclic orpolycyclic, but especially a monocyclic, optionally substituted aromatichydrocarbon residue, for example, an optionally substituted naphthylgroup or in the first place an optionally substituted phenyl group. Suchgroup may be substituted, for example, by optionally substitutedhydrocarbon residues, such as lower alkyl, for instance methyl, ethyl orisopropyl, as well as trifiuoromethyl, phenyl or phenyl-lower alkyl, forexample, benzyl or phenylethyl, or functional groups, such as free orfunctionally modified carb'oxyl groups, for example, carboxyl, loweralkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, alsocarbamoyl groups or cyano, optionally functionally modified, such asesterified, hydroxyl groups, for example, halogeno, such as fluoro,chloro or bromo, or etherified hydroxyl or mercapto groups, such aslower alkoxy, for example, methoxy, ethoxy, propoxy, isopropyloxy,butyloxy or tertiary butyloxy, nitro groups and/or optionallysubstituted amino groups, such as di-lower alkylamino, for example,dimetbylamino or diethylamino, or lower alkanoylamino, for example,acetylamino.

The methyl portion of an arylcarbonylmethyl residue R is preferablyunsubstituted, but it may also contain an organic residue, for example,an optionally substituted aliphatic hydrocarbon residue, such as loweralkyl, for example, methyl, ethyl, propyl, isopropyl, butyl or tertiarybutyl, or an optionally substituted cycloaliphatic, aromatic 0raraliphatic hydrocarbon residue, such as optionally substitutedcycloalkyl, for example, cyclohexyl, or a further aryl or araliphaticgroup, for example, optionally substituted phenyl, as well as optionallysubstituted phenyl-lower alkyl, for example, benzyl.

The arylcarbonylmethyl group R, is preferably the unsubstituted phenacylgroup, though it may also be a phenacyl group whose aromatic portion issubstituted, for example, by lower alkyl, such as methyl, lower alkoxy,such as methoxy, or halogeno, for example, fluoro, chloro or bromo.

The treatment with a chemical reducing agent is carried out in thepresence of at least one mole of water, under mild conditions, ifnecessary while heating, but generally at room temperature or even withcooling.

Chemical reducing agents are especially appropriate reducing metals, aswell as reducing metal compounds, for example, metal alloys or amalgams,especialy those which in the presence of a hydrogen donor form nascenthydrogen, furthermore strongly reducing metal salts.

Especially suitable are zinc, zinc alloys, for example, zinc-copper, orzinc amalgam, also magnesium, using zinc, for example, advantageously inthe presence of an acid, such as an organic carboxylic acid, forexample, a lower alkanecarboxylic acid, in the first place acetic acid,with the addition of water, or of anaqueous alcohol, such as a loweralkanol, for example methanol, ethanol or isopropanol, which may be usedin combination with an organic carboxylic acid, e.g. acetic acid, andalkali metal amalgams, such as sodium amalgam or potassium ence'o'f "amoist (iLeT aqueous) solvent, suchas diethyl ether or a lower alkanol.

Strongly reducing metal salts are in the first placechromium-II-compounds, for. example, chromium'II- chloride orchromium-II-acetate, which1 are preferably used in the presence of anaqueous medium containing water-miscible organic solvents, such as.lower alkanols, lower alkanecarboxylic acids or ,ethers, for example,methanol, ethanol, acetic acid, tetrahydrofuran, dioxane, ethyleneglycoldimethyl ethenor diethyleneglycol dimethyl ether,-or a carboxylic acidamide, forexample, dimethylformamide. i

-It has been found that the present process may be carried out underextremely mild conditions and especially withoutv the formation ofundesired by-products, as may be formed, .for instance, when a compoundof the Formula H-isused, in which X represents a 2,2,2-trichloroethyloxygroup, for example, through reductive dehalogenation.

If-desired, the 2-hydroxyl group in a compound accessible by thepresentprocess may .be acylated in the known manner, using for this purpose anyone of the usual acylating agents, such as an acid or a' reactivederivative,

thereof, the, former, for instance, in the presence of an appropriatecondensing agent, such as a carbodiimide, for example, 'dicyclohexylcarbodiimide, and the latter, if necessary, in the presence of a basicreagent, such as an organic tertiary base, for example, triethylamine;or pyridine. Reactive derivatives of acids are their anhydrides,including the inner anhydrides such as ketenes, or isothiocyanates, ormixed anhydrides (for example, those formed with halogenoformic acidesters, for example chloroformic acid ethyl ester, or halogeno-lower'alkanoic acid halides, e.g. trichloroacetyl chloride), also acidhalides, especially chlorides, or reactive esters, such as esters ofacids with alcohols or phenols containing electron-attracting groupings,as well as with N-hydroxy compounds, for example, cyanomethanol,p-nitrophenol or N-hydroxysuccinimide. The acylating reaction may beperformed in the presence or absence of solvents or solvent mixtures, ifnecessary, with cooling or heating, under increased pressure and/or inan inert gas, for example,

under nitrogen.

"In an-acyl group AC of a compound obtained according to the presentprocess protected functional groups may be liberated in the usualmanner, for example, by

according to conventional methods, for example, by formation of mixtureof diastereoisomeric salts with optically active salt-forming agents,separation of the mixture' into the diastereoisomeric salts andconversion of the iso-' lated salts into the free compounds, or by-fractionalcrystallization from optically active solvents.

The present invention includes also any modification of the process, inwhich a resulting intermediate is usedas starting material and anyremaining steps are carried out with it,.or the process is interruptedat 'a'ny stage thereof; it is also possible to use starting materials inform of derivatives, for example, salts, thereof or to form them.

in situ.

The invention includes also any new intermediate as well as processesfor the manufacture thereof. v

Preferred starting materials and reaction conditions are those, whichlead to the compounds mentioned below as being specially preferred; theymay be in the form of isomer mixtures or of pure isomers.

Preferred starting materials and products of the Formulae II and I,respectively are those, in which a group Ac is in the first place-theacyl residue of an organic carboxylic acid, especially the acyl residueof an optionally substituted aliphatic, cycloaliphatic,cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic orheterocycIyl-aliphatic carboxylic acid or is the acyl residueof a carbonic acid semi-derivative.

.The aliphatic residue of an aliphatic carboxylic acid, whichtermincludes also'formic acid, is an optionally substituted aliphatichydrocarbon residue, such as alkyl, alkenyl or alkinyl, especiallylower-alkyl or lower alkenyl or lower alkinyl, which may contain, forexample, up to 7, preferaby up to 4 carbon atoms. Such residues may, ifdesired, be substituted by one, two or several functional groups, forexample, free, etherified or esterified hydroxyl or mercapto groups,such as lower alkoxy, lower alkenyloxy,. lower alkylenedioxy, optionallysubstituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto oroptionally substituted phenylmercapto or phenyl-lower alkylrnerc apto,lower alkoxycarbonyloxy or lower alkanoyloxy, as wellas by halogeno ornitro, or by optionally substituted amino groups, acyl, such as loweralkanoyl, onoptionally functionally modified carboxyl, such ascarbo-lower alkoxy, optionally N-substituted carbamoyl or cyano.

A cycloaliphatic or cyloaliphatic-aliphatic residue of an appropriatecarboxylic acid is an optionally substituted cycloaliphatic orcycloaliphatic-aliphatic hydrocarbon residue, for example, monocyclic,bicyclic or polycylic cycloalkyl or cycloalkenyl, or cycoalkylorcycloalkenyl-lower alkyl or -lower alkenyl, in which cycloalkyl containsup to 12, such as 3 to 8, or preferably 3 to 6 ring carbon atoms,whereas cycloalkenyl contains, for example, up to 12, such as 3 to 8,especially 5 to 8, preferably 5 or 6 ring carbon atoms, and contains 1or 2 double bonds, and the aliphatic portion of acycloaliphatic-aliphatic residue may contain, for example, up to 7,prefer- I ably up "to 4 carbon atoms. The above-mentioned cycloaliphaticor cycloaliphatic-aliphatic residues may, if desired, be mono-, diorpolysubstituted, for example, by optionally substituted aliphatichydrocarbon residues, such as those mentioned above, for example,optionally substituted lower alkyl, or, for example, as theabovesubstituted lower alkyl, or, for example, as the aboveresidue, forexample, a mono-, bior polycyclic aromatic hydrocanbonresidue,especially a phenyl or a biphenylyl, as well as naphthyl residue, whichmay be mono-, dior polysubstituted, for example, like theabove-mentioned aliphatic or cycloaliphatic hydrocarbon residues.

The araliphatic residuein an araliphatic carboxylic acid is,for-example, an optionally substituted araliphatic hydrocarbon residue,such as an optionally substituted araliphatichydrocarbon residue, suchas an optionally substituted aliphatic hydrocarbon residue containing,for example, up to three, optionally substituted mono-, bior polycyclicaromatic hydrocarbon residues, and is in the first place phenyl-loweralkyl or -lower alkenyl or lower alkinyl; such residues contain, forexample, 1 to 3 phenyl groups and may be mono-, dior polysubstituted inthe aromatic and/or aliphatic portion, for example, like theabove-mentioned aliphatic and cycloaliphatic residues.

Heterocyclic residues in heterocyclic or heterocyclyl aliphaticcarboxylic acids are especially mono-, bior polycyclic aza-, thia-,oxa-, thiaza-, thiadiaza-, oxaza-,

diaza-, triazaor tetrazacyclic residues of aromatic character,v-whichmay be mono-, dior polysubstituted, for example, like theafore-mentioned cycloaliphatic residues. Thealiphatic portion of aheterocyclyl-aliphatic residue may have, for example, the meaningindicated above for the corresponding cycloaliphatic-aliphatic oraraliphatic residue.

The acyl radical of a carbonic acid semi-derivative is preferably theacyl radical of a corresponding semi-ester, in which the esterifyingorganic residue represents an optionally substituted aliphatic,cycloaliphatic, aromatic or araliphatic hydrocarbon residue or aheterocyclyl-aliphatic residue, in the first place the acyl radical of alower alkyl semi-ester of carbonic acid, which may be substituted,preferably in the aor fi-position (that is to say a loweralkoxy-carbonyl residue, which may be substituted in the lower alkylportion, preferably in oc-Or ,8- position), and a lower alkenyl,cycloalkyl, phenyl or phenyl-lower alkyl semi-ester of carbonic acid,which may be substituted in the lower alkenyl, cycloalkyl, phenyl orpheny-lower alkyl portion (that is to say a lower alkenyloxy-carbonyl,cycloalkoxy-carbonyl, phenyloxycarbonyl or phenyl-lower alkoxy-carbonylresidue which may be substituted in the lower alkenyl, cycloalkyl,phenyl or phenyl-lower alkyl portion). Acyl radicals of a carbonic acidsemi-ester may also be corresponding residues of lower alkyl semi-estersof carbonic acid, in which the lower alkyl portion contains aheterocyclic group, for example, one of the above-mentioned heterocyclicgroups of aromatic character, in which both the lower alkyl residue andthe heterocyclic group may be substituted; such acyl radicals are loweralkoxy-carbonyl groups, in which the lower alkyl portion may besubstituted and contains an optionally substituted heterocylic group ofaromatic character.

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl sec. butyl, tert.-butyl, pentyl, isopentyl, hexyl, isohexyl orn-heptyl, whereas lower alkenyl may be, for example, vinyl, allyl,isopropenyl, 2- or 3- methallyl or B-butenyl, and lower alkinyl is, forexample, propargyl or 2-butinyl.

Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl or adamantyl; cycloalkenyl is, for example, 2-or 3-cyclopentenyl, 1-, 2- or 3- cyclohexenyl or 3-cycloheptenyl or2-cyclopropenyl. Cycloalkenyl-lower alkyl or -lower alkenyl is, forexample, cyclopropyl-, cyclopentyl-, cyclohexylor cycloheptylmethyl,-1,1- or -l,2-ethyl, -1,1-, -1,2- or -l,3-propyl, -vinyl or -allyl,whereas cycloalkenyl-lower alkyl or -lower alkenyl group is, forexample, 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 1,2-ethyl, -1,l-, -1,2-or -1,3-'propyl, -vinyl or -allyl.

Naphthyl is 1- or 2-naphthyl, whereas biphenylyl is, for example,4-biphenylyl.

Phenyl-lower alkyl or phenyl-lower alkenyl is, for example, benzyl, 1-or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl,styryl or cinnamyl.

Heterocyclic residues are, for example, monocyclic monoaza-, monothiaormonooxacyclic residues of aromatic character such as pyridyl, forexample 2-, 3- or 4- pyridyl, thienyl, for example, Z-thienyl, or furyl,for example, 2-furyl, or bi-cyclic monoazacyclic residues of aromaticcharacter, such as quinolinyl, for example 2- quinolinyl or4-quinolinyl, or iso-quinolinyl, for example, l-isoquinolinyl, ormonocyclic thiaza-, thiadiaza-, oxaza-, diaza-, triazaor tetraazacyclicresidues of aromatic character, such as oxazolyl, isoxazolyl, thiazolyl1,2,4- or 1,3, 4-thiadiazolyl, isothiazolyl, pyrimidinyl,1,2,4-triazolyl or 1- or S-tetrazolyl. Heterocyclyl-aliphatic residuesare heterocyclyl-lower alkyl or -lower alkenyl residues, especiallythose containing the above-mentioned residues.

Etherified hydroxyl groups are in the first place lower alkoxy, forexample methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,sec-butyloxy, tert.-butyloxy, n-pentyloxy or tert.-pentyloxy, as well assubstituted lower alkoxy, such as halogeno-lower alkoxy, especially2-halogeno-lower alkoxy, for example, 2,2,2-trichloroethoxy or2-iodoethoxy, furthermore lower alkenyloxy, for example, vinyloxy orallyloxy, lower alkylenedioxy, for example, methyleneor ethylenedioxy,as well as isopropylidenedioxy, cycloalkoxy, for example,cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyloxy, phenylloweralkoxy, for example, benzyloxy or lor 2-phenylethoxy, or lower alkoxysubstituted by monocyclic monoaza-, monooxaor monothia-cyclic groups ofaromatic character, such as pyridyl-lower alkoxy, for example, 2-pyridylmethoxy, furyl-lower alkoxy, for example, furfuryloxy, orthienyl-lower alkoxy, for example, 2-thienyloxy.

Etherified mercapto groups are lower alkylmercapto, for example,methylmercapto or ethylmercapto, phenylmercapto, or phenyl-loweralkylmercapto, for example, benzylmercapto.

Esterified hydroxyl groups is in the first place halogeno, for example,fiuoro, chloro, bromo or iodo, and also lower alkanoyloxy, for example,acetyloxy or propionyloxy.

Substituted amino groups are monoor disubstituted amino groupscontaining as substituents in the first place optionally substitutedmonoor divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic hydrocarbon residues or acyl groups. Such aminogroups are especially lower alkylamino or di-lower alkylamino, forexample, methylamino, ethylamino, dimethylamino or diethylamino, orlower alkyleneamino, optionally interrupted by hetero atoms, such asoxygen, sulfur or nitrogen atoms (of which the latter may besubstituted, for example, by lower alkyl), such as pyrrolidino,piperidino, morpholino, thiomorpholino or 4-methylpiperazino, oracylamino, especially lower alkanoylamino, such as acetylamino orpropionylamino.

Lower alkanoyl residue is, for example, acetyl or propionyl.

Lower alkoxy-carbonyl is, for example, methoxycarbonyl, ethoxycarbonyl,n-propyloxy-carbonyl, isopropyloxycarbonyl, tert.-butyloxycarbonyl ortert.-pentyloxycarbonyl.

Optionally N-substituted carbamoyl groups are, for example, N-loweralkylor N,N-di-lower alkyl-carbamoyl, such as N-methyl-, N-ethyl-,N,N-dimethylor N,N-diethylcarbamoyl.

Lower alkenyloxy-carbonyl is, for example, vinyloxycarbonyl, whereascycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, in which cycloalkylor phenyl-lower alkyl has the above meaning, is, for example,adamantyloxycarbonyl, benzyloxycarbonyl or diphenylmethoxycarbonyl orm-4-biphenylyl-a-methyl-ethoxy-carbonyl. Lower alkoxy-carbonyl, in whichthe lower alkyl residue contains, for example, a monocyclic monoaza-,monooxaor monothiacyclic group, is, for example, furyl-loweralkoxycarbonyl, such as furfuryloxy-carbonyl, or thienyl-loweralkoxycarbonyl, for example, 2-thienyloxy-carbonyl.

O-esters of compounds of the Formula I are those with organic sulphonicacids, especially with aliphatic or aromatic sulphonic acids, in whichaliphatic and aromatic residues have the above meaning, such as loweralkanesulphonic, for example, methanesulphonic or ethanesulphonic acids,or arylsulphonic, for example, benzenesulphonic ortoluenesulphonic'acids, and especially with organic carboxylic acids,such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic,araliphatic, heterocyclic or heterocyclyl-aliphatic carboxylic acidswhich contain the afore-mentioned organic residues, such as loweralkanecarboxylic acids which may be substituted, for example, byhalogeno, being, for example formic, propionic, pivalic, diethylaceticor chloroacetic acid, cycloalkanecarboxylic acids, such ascyclopentaneor cyclohexanecarboxylic acid, cycloalkyl-loweralkanecarboxylic acids, such as cyclohexylacetic acid, aromatic andaraliphatic carboxylic acids, in which the aromatic ring may besubstituted, for example, by lower alkyl or lower alkoxy, halogeno,nitro, carboxyl, lower alkoxy-carbonyl, carbamoyl or cyano, being, forexample benzoic, naphthoic, phenylacetic,-phenylpropionic or cinnamicacid, or carboxylic acids containing optionally substituted heterocyclicresidues, for example, pyridine-, furanor thiophenecarboxylic acids,such as 2'pyridylor 2-thienylacetic acid, as well as3-(2-furyD-propionic acid.

Especially valuable are penam compounds of the formula resulting fromthe present process, in which Ac stands for an acyl radical occurring ina pharmacologically active or biosynthetically accessible N-acylderivative of 6- amino-penicillanic acid or of 7-amino-cephalosporanicacid, for example, the residue of the formula in which m is 0, 1, 2, 3or 4, preferably 1, and one carbon atom of the preferably linearalkylene residue of the formula -(C H may be substituted by anunsubstituted or substituted amino group, a free, etherified oresterified hydroxyl or mercapto group or a free or functionally modifiedcarboxyl group, for example, by one of the aforementioned groups of thistype, and wherein Y stands for an aromatic or cycloaliphatic hydrocarbonresidue which may be substituted in the nucleus, for example, by thesubstituents indicated for the above alkylene radical, or by sulpho ornitro groups, or for a heterocyclic residue, the latter being preferablyof aromatic character, or for a hydroxyl or mercapto group etherified byan optionally substituted aromatic or cycloaliphatic hydrocarbon residueor a heterocyclic residue, the latter preferably being of aromaticcharacter, and represents, for example, 2,6 dimethoxybenzoyl,tetrahydronaphthylcarbonyl, Z-methoxynaphthylcarbonyl,Z-ethoxynaphthylcarbonyl, phenylacetyl, phenyloxyacetyl,phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl,a-phenyloxyphenylacetyl, u-methoxy-phenylacetyl, a-methoxy-3,4-dichlorophenylacetyl, a cyanophenylacetyl, phenylglycyl (containing anoptionally protected amino group), benzyloxycarbonyl, benzylthioacetyl,benzylthiopropionyl, hexahydrobenzyloxycarbonyl, cyclopentylcarbonyl,aaminocyclopentylcarbonyl or a-amino-cyclohexylcarbonyl (containing anoptionally protected amino group), 2- thienylacetyl,a-cyano-Z-thienylacetyl, u-amino-Z-thienyL acetyl (containing anoptionally protected amino group), S-thienylacetyl, 2-fu1'ylacetyl,2-pheny1- 5 methyl isoxazolyl-carbonyl or 2-(2-chlorophenyl) 5methyl-isoxazolylcarbonyl group, or represents a residue of the formulan zn+1 0r a 2n 1 in which n is 0 or an integer up to 7, and the chainmay be linear or branched and optionally interrupted by oxygen or sulfurand/or may be substituted, for example, by halogeno, trifluoromethyl,free or functionally modified carboxyl, such as cyano, or free orsubstituted amino or nitro groups, and represents, for example,propionyl, butyryl, hexanoyl, octanoyl, butylthioacetyl, acrylyl,crotonyl, Z-pentenoyl, allylthioacetyl, chloroacetyl, 3-chloropropionyl,3-bromopropionyl, aminoacetyl, 2-carboxypropionyl, cyanoacetyl or2-cyano-3-dimethylacrylyl, or represents a residue of the formula Zr-NHCO, in which Z stands for an optionally substituted aromatic oraliphatic hydrocarbon residue, especially a lower alkyl residueoptionally substituted by lower alkoxy and/or halogeno. such as2-chloroethylcarbamoyl. The acyl group Ac is especially a monocyclicarylacetyl or aryloxyacetyl or a lower alkanoyl or lower alkenoylresidue, which may be interrupted by a sulfur atom or substituted bycarboxyl and/or amino. Such residues are, for example,4-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl,allylmercaptoacetyl, n-butylmercaptoacetyl or 5- amino-S-carboxyvaleryl,and primarily phenylacetyl or phenyloxyacetyl, or may also be an acylradical, which is eas y s minabla especially der acidic co d t o s, uch

as the acyl radical of an easily removable semi-ester of carbonic acid,such as a lower alkoxycarbonyl residue easily eliminable under acidicconditions, for example, on treatment with trifiuoroacetic acid, e.g.tert.-butyloxycarbonyl or tert. pentyloxycarbonyl, cycloalkoxycarbonyl,for example, adamantyloxycarbonyl, phenyl-lower alkoxy-carbonyl, forexample, diphenylmethoxycarbonyl, as well as m-4-biphenylyl-a-methylethoxy carbonyl, or furyl-lower alkoxycarbonyl, for example,furfuryloxycarbonyl.

The compounds accessible by the present process are useful as startingmaterials for the manufacture of other compounds which may be used aspharmacologically active or as intermediate products; their further usehas been described and illustrated by examples in the Pat. No. 3,705,160(application No. 842,028 filed July 15, 1969 by Karl Heusler et a1.) andin German Auslegeschrift No. 1,935,637.

The starting materials of the Formula 11 used in the present process maybe manufactured, for example, by converting an acid compound of theformula in which Ac represents the acyl radical of an organic carboxylicacid, in which free functional groups, such as hydroxyl, mercapto andespecially amino and carboxyl groups are preferably protected, and Rstands for a car boxyl group -C(==O)OH (Compound IIIa) or a salt thereofinto the corresponding acid azide compound of the Formula III, in whichR stands for the azidocarbonyl residue C(=O)-N (Compound IIIb), theresulting compound is converted (with the elimination of nitrogen) intothe corresponding isocyanate compound of the Formula HI, in which Rrepresents the isocyanato group N=O=O (Compound IIIc), and issimultaneously or subsequently treated with a compound of the formulaHO--R,, (IV) and, if desired, a resulting compound is converted intoanother compound of the Formula II, and/ or if desired, a resultingisomer mixture is resolved into the component isomers.

The conversion of an acid Compound IIIa or a suitable salt, especiallyan ammonium salt, thereof into the corresponding acid azide IIIb may beperformed, for example, by conversion into a mixed anhydride (forexample, by treatment with a lialoformic acid lower alkyl ester, such asethyl chloroformate, in the presence of a basic medium, such astriethylamine) and treatment of such an anhydride with an alkali metalazide, such as sodium azide, or an ammonium azide, for example,benzyltrimethylammonium azide. The resulting acid azide Compound IIIbcan be converted into the desired isocyanate Compound 111s in thepresence or absence of an alcohol compound of the Formula IV under thereaction conditions, for example, by heating; as a rule, the isocyanateCompound IIIc need not be isolated and can be converted directly intothe desired starting material in the presence of the compound of theFormula IV.

If desired or required, the reaction with an alcohol of the Formual IVmay be carried out in an inert solvent, for example, in an optionallyhalogenated hydrocarbon, such as carbon tetrachloride, chloroform ormethylenechloride, or in an aromatic solvent, such as benzene, tolueneor chlorobenzene, preferably at an elevated temperature.

In a resulting starting material process an acyl radical Ac may beeliminated in known manner, for example, by treatment with anappropriate halogenating agent, such as phosphorus pentachloride,reaction of the imide chloride with an alcohol, such as a lower alkanol,and decomposition of the imino ether, preferably under acidicconditions. The acyl residue of a suitable s mester of carbonic acid,such as a lower alkoxycarbonyl residue capable of being eliminated underacidic conditions, for example, the tert.-butyloxycarbonyl,tert.pentyloxycarbonyl, admantyloxycarbonyl or diphenylmethoxycarbonylresidue, can be eliminated, for example, by treatment withtrifluoroacetic acid. Protected functional groups in an acyl residue Acof a resulting compound may be liberated in the usual manner, forexample, by hydrolysis or reduction or by treatment with an acid.

A free amino group in a starting material accessible in the mannerdescribed above may be acylated by known methods, such as, for example,the free hydroxyl group in a compound of the Formula I, that is to sayby treatment with a free or reactive, functionally modified carboxylicacid, for example, with an acid chloride or anhydried, optionally in thepresence of a condensing agent.

The invention includes also the new starting materials of the FormulaII, in which X represents the residue of the formula OR,, wherein R hasthe meaning defined above, especially penam compounds of the formula inwhich Ac has the meaning indicated above and stands especially for amonocyclic arylacetyl or aryloxyacetyl or a lower alkanoyl or loweralkenoyl residue, such as the 4-hydroxyphenylacetyl, hexanoyl, heptanoylor 2 hexenoyl and in the first place for phenylacetyl orphenyloxyacetyl, or for an acyl residue of a carbonic acid semiester,which is easily eliminated under acidic conditions, such as acorresponding lower alkoxycarbonyl, cycloalkoxycarbonyl, phenyl-loweralkoxycarbonyl or furyl-lower alkoxycarbonyl residue, being eliminated,for example, by treatment with trifluoroacetic acid.

The following examples illustrate the invention.

EXAMPLE 1 A solution of 4.84 g. of2,2-dimethyl-3-phenacyloxycarbonylamino-6-phenyloxyacetylamino-penam in50 ml. of tetrahydrofuran is mixed with 75 ml. of aqueous acetic acid of90% strength. The mixture is cooled to 0 C., and while stirringvigorously it is mixed portionwise within 15 minutes with 12 g. of zincdust, then allowed to warm up to room temperature and stirred for anadditional 60 minutes. The unreacted iznc dust is filtered oflf on aBuechner funnel containing a layer of a diatomaceous earth preparation.The filter residue is twice suspended in methylenechloride, once morefiltered and rinsed with methylenechloride. The combined filtrates areevaporated to dryness under reduced pressure at as low a temperature aspossible and the residue is taken up in 300 ml. of methylenechloride and150 ml. of a 0.5-molar aqueous dipotassium hydrogenphosphate solution.The isolated aqueous phase is extracted twice with 100 ml. portions ofmethylenechloride and the combined organic solutions are washed with 100ml. of the above-mentioned phosphate bufier and twice with 100 ml. eachtime of a concentrated aqueous sodium chloride solution, then dried overanhydrous magnesium sulphate and evaporated under reduced pressure.

The residue is placed to a chromatography column with silica gel(containing about of water) as adsorbent. The column is washed withmethylenechloride to remove acetophenone; 9:1- and 4:1-mixtures ofmethylenechloride and ethyl acetate elute the 3-hydroxy-2,2-dimethyl-6-phenyloxyacetylamino-penam of the formula melts at 6270 C.; thin-layerchromatogram (on silica gel): R =0.35 (system: benzene and ethyl acetate1:1); infrared absorption spectrum (in methylenechloride: characteristicbands at 2.93;, 3.09;, 5.65p, 5.96 1, 629p, 6.65m 6.75,u, 8.57 9.27 i,10.00; and 11.95,".-

The starting material may be prepared as follows:

While stirring and cooling at --l0 C., a solution of 2.625 g. ofpenicillin-V in 30 ml. of tetrahydrofurane is mixed with 5.31 ml. of a10 mL-solution of 2 ml. of triethylamine in tetrahydrofurane. Then, 3.6ml. of a 10 mL-solution of 2 ml. of ethyl chloroformate in tetrahydrwfurane are slowly added at 10 C. and on completion of the addition themixture is stirred for 90 minutes at 10 t0 '5 C.

The reaction mixture is treated with a solution of 0.51 g. of sodiumazide in 5.1 ml. of water, stirred for 30 minutes at 0 to --5 C.,diluted with 150 ml. of ice water and extracted three times withmethylenechloride; the organic extracts are washed with water, dried andevaporated at 25 C. under reduced pressure, to furnish the amorphouspenicillin-V azide as a faintly yellowish oil; infrared absorptionspectrum (in methylenechloride): characteristic bands at 3.04;, 4.705.60 5.82, (shoulder), 5.93% 6.26% 6.71,u., 8.50 1. and 9.40/L.

A solution of 2.468 g. of the penicillin-V azide in 30 ml. of benzene isheated for 30 minutes at C. The resulting crude3-isocyanato-2,2-dimethyl-6-phenyloxyacetylamino-penam can be obtainedby evaporating the solution under reduced pressure; infrared absorptionspectrum (in methylenechloride): characteristic bands at 3.03 4.46 5.59i, 5.93m 6.26,u, 6.62 6.70 7.53 8.28 8.53;, 9.24;. and 9.40m

A solution of 6.6 g. of crude 3-isocyanato-2,2dimethyl--6-phenyloxyacetylamino-penam in ml. of absolute methylenechloride ismixed with 2.6 g. of phenacyl alcohol. The golden yellow solution iskept for 30 minutes at room temperature (the characteristic isocyanateband at 4.45 in the infrared spectrum can no longer be detected; 40%solution in methylenechloride) and then evaporated to dryness. The foamyresidue is chromatographed on a column of 300 g. of silica gel, theexcess phenacyl alcohol (melting at -8-6" C. after recrystallizationfrom a mixture of methylenechloride and cyclohexane) being eluted withmethylenechloride. The 2,2- dimethyl 3phenacyloxycarbonylamino-6-phenyloxyacetylamino-penam of the formuladin-bu Gemini-Na s is eluted with 4: 1- and lzl-mixtures ofmethylenechloride and ethyl acetate and recrystallized from a mixture of11' methyl acetate and cyclohexanone. The product is obtained in form ofcolorless, felted needles and melts at 168-169 C. (uncorrected);

(c. =0.991 in chloroform); thin-layer chromatography (on silica gel): R=0.58 (system: toluene/acetone 1:1), R =0.46 (system: toluene/acetone3:1) and Rf=0-51 (system: toluene/ethyl acetate 1:1); ultravioletabsorption spectrum (in chloroform); A =276 m; (e==2500), 270 m;(-e=2700) and 245 m; (e -34800); A =292 111; (e=1000); and A =273 m;(e=2150) and 266 m; (e=2500); infrared absorption spectrum:characteristic bands at 2.90;, 3.39;, 5.57;, 5.74;, 5.86;, 6.23;, 6.62;,6.67; (shoulder), 7.27;, 8.21; (broad), 8.46;, 9.25; and 9.34;(shoulder) (in methylenechloride), and'at 2.93;, 2.98;, 5.67;, 5.74;,5.80;, 5.91;, 6.23;, 6.42; and 6.62; (in mineral oil).

EXAMPLE 2 A solution of 2.34 g. of2,2-diethyl-3-phenacyloxycarbonylamino-6-phenylacetylamino-penam in 25ml. of tetrahydrofurane is mixed with 37 m1. of aqueous acetic acid of90% strength, cooled to 0 C. and treated portionwise within 10 minuteswith 6 g. of zinc dust while stirring vigorously. The mixture is stirredfor 20 minutes and the excess zinc dust is then filtered off through alayer of a diatomaceous earth preparation. The filter residue is stirredthree times with methylenechloride and filtered. The combined filtratesare cautiously evaporated to dryness under reduced pressure and theresidue is taken up in 150 m1. of methylenechloride and 75 ml. of a0.5-molar aqueous dipotassium hydrogenphosphate solution. The aqueousphase is separated and extracted twice with 50 ml. each ofmethylenechloride. The organic extracts are washed with 50 ml. of thedipotassium hydrogenphosphate solution and twice with 50 ml. each of asaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulphate and the solvent is evaporated under reduced pressure.The residue is chromatographed on 50 times its own weight of silica gel(to which 7% of water has been added). Acetophenone is eluted withmethylenechloride; the 3-hydroxy-2,2-dimethyl-6-phenylacetylamino-penamof the formula is eluted with methylenechloride containing 15 to 20% ofmethyl acetate and obtained as a colorless oil; infrared absorptionspectrum (in methylenechloride): characteristic bands at 2.90;, 3.05;,5.64;, 5.99;, 6.70; and 9.28;. i

The starting material may be prepared as follows:

A solution of 17.3 g. of 3-isocyanate-2,2-dimethyl-6-phenylacetylamino-penam in 150 ml. of absolute benzene is mixed with 6.5g. of phenacyl alcohol. The golden yellow solution is kept for 16 hoursat room temperature, after which time no isocyanate band at 4.4; can bedetected in the infrared spectrum (solution of about 4% strength inmethylenechloride). The reaction solution is evaporated to dryness underreduced pressure and the residue is chromatographed on a column of 800g. of silica gel. A small quantity of unreacted phenacyl alcohol (MJP.85-86" C.) is washed out with methylenechloride containing 3% of ethylacetate, whereas the 2,2-dimethyl- 3 phenacyloxycarbonylarnino 6phenylacetylaminopenam is eluted with methylenechloride containing ofethyl acetate. The chromatographically uniform fractions are combinedand crystallized from a mixture of acetone and cyclohexane. Thecolorless crystalline product melts at 175178 C. (uncorrected). Theanalytically pure product, obtained from two recrystalliza: tions from amixture of methyl acetate and cyclohexane, melts at 182183 C.(uncorrected); thin-layer chromatogram (on silica gel plates; developedwith iodine vapor): R;=0.59 (system: toluene/ethyl acetate 1:1) R =0.82(system: toluene/acetone 1:1); and R;=0.42 (system: toluene/acetone3:1); [a] =+87:1 (c.=0.985 in chloroform); infrared spectrum:characteristic bands at 2.92;, 5.59;, 5.76;, 5.87;, 5.94;, 6.31;, 6.62;(shoulder), 6.67;, 8.22;, 848;, 9.22;, 10.20; and 10.44; (in methylenechloride) and at 2.96;, 3.02;, 5.59;, 5.86;, 6.02;, 6.25;, 6.45;, 6.58;,7.98;, 8.15;, 8.28;, 9.15;, 9.24;, 9.32;, 1018;, 11.47;, 13.94; and14.58; (in mineral oil) In an analogous manner, choosing the appropriatestarting materials, it is possible to obtain the 3-hydroxy-2,2- dimethyl6 tert.-butyloxycarbonyl-arnino-penam as a colorless oil which, aftercrystallization from a mixture of diethyl ether and pentane, melts at106-110 C. (after sintering a-bove C.) [a] =+:L-1 (c.=0.858 inchloroform), thin-layer chromatogram (silica gel): R about 0.53 (system:benzene/ethyl acetate 1:1); infrared absorption spectrum (inmethylenechloride): characteristic bands at 2.91;, 3.04;, 5.64;, 5.84;,6.68;, 7.33; and 8.60;; from2,2-dimethyl-3-phenacyloxy-carbonylamino-6-tert.-butyloxycarbonyl-amino-penam.

EXAMPLE 3 A solution of 0.14 g. of 3-hydroxy-2,2-dimethyl-6-phenyloxyacetylamino-penam in 2 ml. of anhydrous benzene is mixed with 1ml. of acetic acid anhydride and 0.2 m1. of pyridine and heated for 2hours at 50 C. The mixture is then evaporated under reduced pressure andthe residue is purified by chromatography on 1 g. of silica gel (washedwith acid). Elution is carried out with 10 ml. of benzene and 40 ml. ofa 19:1-mixture of benzene and ethyl acetate, to furnish the pure3-acetyloxy-2,2-dimethyl-6-phenyloxyacetylamino-penam, which, aftercrystallization from a mixture of diethyl ether and pentane andrecrystallization from diethyl ether, melts at 129l31 C.; [.oc]='+85'i'1 (c.=1.135 in chloroform); infrared absorption spectrum (inmethylenechloride); characteristie bands at 3.05;, 5.61;, 5.74;, 5.94;,6.28;, 6.64;, 6.72;, 8.32; and 9.62;.

EXAMPLE 4 A solution of 0.132 g. of 3-hydroxy-2,2-dimethyl-6-phenyloxyacetylamino-penam in 2 of benzene is mixed with 0.75 ml. of a10 mL-solution of 1 ml. of benzoyl chloride in benzene and with 0.1 ml.of pyridine and the mixture is stirred for 20 hours at room temperature,then diluted with benzene and washed successively with 0.5 N-hydrochloric acid, a dilute aqueous sodium hydrogencarbonate solutionand water; the aqueous washings are washed with benzene. The combinedbenzene solutions are dried and evaporated under reduced pressure. Theresidue is chromatographed on 2.5 g. of silica gel washed with acid;nonpolar impurities are washed out with 60 ml. of benzene. With 15 ml.of a 9:1 mixture of benzene and ethyl acetate the3-benzoyloxy-2,2-dimethyl-6-phenyloxyacetylamino-penam is eluted andobtained as a faintly yellowish amorphous product, infrared absorptionspectrum (in methylenechloride): characteristic bands at 3.05;, 5.60;,5.80;, 5.92;, 6.26;, 6.62;, 6.70;, 8.28;, 8.50;, 9.20;, 9.36; and10.20;.

EXAMPLE 5 A solution of 0.14 g. of 3 hydroxy 2,2 dimethyl-6-phenylacetylamino-penam in 2 ml. of anhydrous benzene is mixed with 1ml. of acetic acid anhydride and 0.2 ml. of pyridine; the mixture isheated for 2 hours at 50 C. and then concentrated under reducedpressure. The residue is filtered through a column of 10 g. of silicagel washed with acid. With 30 ml. of a 19:1-mixture of benzene and ethylacetate and 10 ml. of a 9:1-mixture of benzene and 3 ethyl acetate, theamorphous 3 acetyloxy 2,2 dimethyl- 6-(N-phenylacetylamino)-penam iseluted; infrared absorption spectrum (in methylene chloride):characteristic bands at 3.06,, 5.62, 5.76,:1, 5.98 1, 6.70n, 7.35,u.,8.28;. and 9.60g. The product contains about 10% of the compoundepimeric in 2-position.

EXAMPLE 6 A solution of 0.123 g. of 3 hydroxy 2,2 dimethyl-6-phenylacetylamino-penam in 2 ml. of anhydrous benzene is mixed with 0.1ml. of pyridine and with 0.75 ml. of a 10 mL-solution of 1 ml. ofbenzoylchloride in benzene, and the mixture is stirred for 16 hours atroom temperature, then diluted with benzene and washed with 0.5N-hydrochloric acid, a dilute aqueous sodium hydrogencarbonate solutionand water; the aqueous washings are extracted with benzene. The organicsolutions are combined, dried and concentrated under reduced pressure.The residue is chromatographed on 2.5 g. of silica gel, washed withacid. The 3 benzoyloxy 2,2 dimethyl 6 phenylacetylamino-penam is elutedwith a 19:1- and a 9zl-mixture of benzene and ethyl acetate in form of ayellow oil; infrared absorption spectrum (in methylene-chloride):characteristic bands at 3.03,u, 5.60;, 5.80 11, 5.97p, 6.65 9.18 1, 9.344, 9.72 1 and 10.15p..

We claim:

1. A process for the manufacture of compounds of the formula Hit; Ac Ns/ OH: (I)

in which Ac is a member selected from the group consisting of loweralkanoyl, lower alkenoyl, phenylacetyl, 4-hydroxy-phenylacetyl,phenyloxyacetyl, carbo-lower alkoxy, carbo adamantyloxy, carbo phenyllower alkoxy and carbo furfuryloxy, wherein a penam compound of theformula NH- i l-X in which X represents the radical of the formula O-Rwherein R represents a monoor bi-cyelic carbocyclic arylcarbonylmethylgroup, in which aryl is unsubstituted or substituted by lower alkyl,lower alkoxy or halogen, is treated under mild conditions with achemical reducing agent selected from the group consisting of zinc, azinc alloy, zinc amalgam or magnesium in the presence of an aqueous acidor an aqueous alcohol, an alkali metal 14 amalgam or aluminum amalgam inthe presence of a moist solvent, and a chromium-II-salt in the presenceof an aqueous solvent, at least one mol of water being present.

2. A process as claimed in claim 1, wherein R represents the phenacylradical.

3. A process as claimed in claim 1, wherein a member selected from thegroup consisting of zinc, zinc-copper and zinc amalgam in the presenceof a member selected from the group consisting of an aqueous loweralkane carboxylic acid and an aqueous lower alkanol is used as thereducing agent.

4. A process as claimed in claim 1, wherein zinc and acetic acid, withthe addition of water, is used as the reducing agent.

5. A process as claimed is claim 1, wherein a chromium-II compound inthe presence of an aqueous medium is used as the reducing agent.

6. A process as claimed in claim 1, wherein the process is carried outin the presence of at least 1 mol of water.

7. A penam compound of the formula H-(JH /C\C AcI IH s H3 (II) in whichAc is a member selected from the group consisting of lower alkanoyl,lower alkenoyl, phenylacetyl, 4- hydroxy phenylacetyl, phenyloxyacetyl,carbo lower alkoxy, carbo adamantyloxy, carbo phenyl lower alkoxy andcarbo furfuryloxy, and R represents a monoor bi-cyclic carbocyclicarylcarbonylmethyl group, in which aryl is unsubstituted or substitutedby lower alkyl, lower alkoxy or halogen.

8. A penam compound as claimed in claim 9 and being 2,2 dimethyl 3phenacyloxycarbonyl-amino-6-phenyloxyacetylamino-penam.

9. A penam compound as claimed in claim 9 and being 2,2 dimethyl 3phenacyloxycarbonyl-amino-6-phenylacetylamino-penam.

10. A penam compound of Formula II as claimed in claim 9, wherein Rrepresents the phenacyl group.

11. A penam compound of Formula II as claimed in claim 9, wherein R isthe phenacyl group and Ac represents a member selected from the groupconsisting of hexanoyl, heptanoyl, 2-hexenoy1, phenylacetyl orphenyloxyacetyl.

References Cited UNITED STATES PATENTS 3,479,339 11/1969 Holdrege260-239.1 3,652,546 3/1972 Cheney et a1. 260239.1 3,652,547 3/ 1972 Wolfet al 260-2391 NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R. 424-27122253 UNITED STATES PATENT OFFICE CERTKFICATE 0F (10BREC'HON Patent No.3, Dated April 3 97 Inventor(s) HEUSLER ET AL It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column l t, claim 8, line 38, delete "9" and substitute Column 14, claim9, line +1, delete "9" and substitute 7 flu-0 Signed and sealed this 5thday of November 1974.

(SEAL) Attest:

MCCOY M. GIBSON JR, C. MARSHALL DANN Attesting Officer Commissioner ofPatents

